Against the Odds, Immune-Based Therapies for HIV Slog Along
By Richard Jefferys
Industry “Leery”
Despite more than two decades of research, there is as yet no approved immune-based therapy (IBT) for HIV infection. And while antiretrovirals continue to course through the developmental pipeline, relatively few potential immunologic interventions are dripping their way toward efficacy trials. This imbalance is partly due to an incomplete understanding of HIV’s effects on the human immune system compared to our detailed knowledge of the viral life cycle. Absent this information, targets for IBTs are typically based on theories regarding pathogenesis and thus are susceptible to failure if a particular theory turns out to be incorrect. (By contrast, a new antiretroviral compound can be targeted to a well understood step in the HIV replication process.)
In addition, several IBTs (including Jonas Salk’s ill-starred therapeutic vaccine candidate, Remune, and the bone marrow stimulant GM-CSF) have progressed to phase III efficacy trials but have failed to show clinical benefit, making industry leery of pursuing compounds that risk a similar fate. It is also difficult to assess the prospective market for IBT given that none is available, while there are years of accumulated data on the sales of antiretroviral drugs. Despite these problems, there are a variety of IBTs in development at the current time. Richard Jefferys prepared this IBT pipeline report for TAGline.
The advent of HAART has led to a resurgence of interest in therapeutic immunization, based on the idea that viral suppression and the attendant immune reconstitution may provide an opportunity to induce new and more effective T-cell responses targeting HIV. The primary goal of these products is to maintain better control of viral replication during HAART interruptions, thereby reducing dependence on drug therapy over the long term. Although this is certainly a desirable outcome, there is as yet no convincing human data showing that therapeutic immunization can improve control of viral load when HAART is withdrawn. Some researchers — including French doyen of immunology Brigitte Autran — are optimistic about the prospects for this approach, while many others remain profoundly skeptical. This area of IBT research has recently been invigorated by the involvement of two large pharmaceutical companies, Merck and GSK, who now have therapeutic vaccine candidates undergoing human testing.
Interleukin-2: Forgotten but Not Gone
Another category of IBTs is comprised of candidates intended to improve overall immune function as opposed to just HIV-specific immunity. The hardy perennial of this class of therapies is interleukin-2 (IL-2), which has been in trials since the mid-1980s. IL-2 belongs to a family of chemical messengers called cytokines that transmit signals between the cells of the immune system. Initially dubbed “T-cell growth factor” due its ability to induce T-cell proliferation, IL-2 is now understood to have more complex effects, including an unexpectedly important role in programmed T-cell death. Many studies have demonstrated that IL-2, administered either intravenously or subcutaneously, can increase peripheral blood CD4 T-cell counts in people with HIV infection. However, questions persist about the functionality of these IL-2-induced CD4 T cells, with one recent ACTG study finding that they did not appear to improve — and may in some cases have diminished — the response to a variety of routine vaccinations (such as hepatitis A vaccine — see TAG’s Basic Science Review, January/February 2003). Side effects such as fever, chills and malaise are also typically associated with IL-2 administration. Nevertheless, it remains possible that the CD4 T-cell increases associated with IL-2 therapy will lead to long term clinical benefit by delaying HIV-induced CD4 T-cell depletion, and this hypothesis is being investigated in two large clinical endpoint trials, SILCAAT and ESPRIT. Preliminary results from these trials should be available in 2005. An engineered and potentially less toxic form of IL-2 known as BAY 50-4798 is also under investigation in a phase I/II trial.
The New Interleukins: IL-7 and IL-15
Studies are planned for two newer members of the cytokine family, IL-7 and IL-15. IL-7 studies in SIV-infected rhesus macaques have shown dramatic increases in peripheral blood CD4 and CD8 T-cell counts, without a concomitant increase in SIV replication. A phase I study is now in the works at the ACTG. IL-15 is a cytokine that can induce T-cell proliferation and enhance virus-specific CD8 T-cell responses in vitro and in rhesus macaques. Higher levels of IL-15 have also recently been associated with enhanced control of HIV viral load after treatment interruption in humans (see TAGline, November 2003). A pilot study of IL-15 administered to SIV-infected cynomolgus macaques was presented at the February 2004 Retrovirus Conference in San Francisco, with preliminary results indicating significant increases in CD8 T-cells counts. Analyses of IL-15’s effect on viral load and SIV-specific immune responses are ongoing. Researchers at the ACTG are also hoping to move IL-15 into human trials in the near future.
Blocking the “Bad” Interleukins: Anti-IL-4 and IL-13
Another IBT strategy involves blocking potentially harmful cytokines. A small biotech company called Regeneron is developing a product called IL-4/IL-13 Trap based on the idea that these cytokines inhibit virus-specific CD8 T-cell responses. Results from a phase I dose-ranging trial in HIV-negative volunteers were presented at the 2004 Retrovirus conference, showing that the construct was well tolerated with a long half-life of 13 days. Further studies in HIV-infected individuals are planned.
Glaxo Dusts Off Something for APCs
- Tucaresol
is a relatively obscure IBT candidate that has languished in GlaxoSmithKline’s HIV drug portfolio since the early 1990s. The drug appears to enhance interactions between antigen-presenting cells and T cells and has been shown to boost cell-mediated immune responses both in mice and in humans. Preliminary data from a phase I trial in 17 HIV-infected individuals were presented at the 2004 Retrovirus conference, demonstrating increases in naive CD4 T-cell counts and the number of T cells containing TRECs (a potential marker for T cells recently produced by the thymus) in the group of participants receiving HAART treatment. Larger studies are now likely.
Two That Target Defective Cellular “Signaling”
Two experimental IBTs aim to influence T-cell function by interacting with signaling molecules on the T-cell surface. One such molecule is CTLA-4, which is upregulated on T cells in HIV infection and associated with the induction of T-cell unresponsiveness or anergy. In June of 2003, the biotech company Medarex launched a phase I trial of an anti-CTLA-4 antibody dubbed MDX-010 in heavily treatment experienced HIV-infected individuals that are failing HAART, with the aim of blocking the suppressive activity of CTLA-4 and thus improving HIV-specific immunity. Results from this study have not yet been presented. Another molecule that is a target for IBTs is CD40. Signaling via CD40 is triggered by CD40 ligand (CD40L) and can potentially enhance the function of otherwise lethargic virus-specific CD8 T cells. The rights to CD40L were held by Immunex, a company that was recently bought by Amgen. The current developmental status of CD40L is unclear as Amgen did not return calls prior to going to press.
IBTs in Development
Information on IBT in development is ever-changing. If you know of any inaccuracies in — or omissions from — this list, please send an e-mail to richard.jefferys@verizon.net.
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Cytokines and Immunomodulators |
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Product |
Manufacturer |
Status |
| interleukin-2 (IL-2) | Chiron | Phase III |
| BAY 50-4798 | Bayer | Phase I/II |
| interleukin-7 (IL-7) | Biotech Inflection Point | Preclinical |
| Interleukin-15 (IL-15) | Amgen (formerly Immunex) | Preclinical |
| IL-4/IL-13 trap | Regeneron Pharmaceuticals | Phase I |
| Serostim (human growth hormone) | Serono | Phase not specified (ACTG 5174) |
| Tucaresol | GlaxoSmithKline | Phase I |
| MDX-010 anti-CTLA4 antibody | Medarex | Phase I |
| Avrend (CD40 ligand) | Amgen (formerly Immunex) | ? |
| Pegasys (peginterferon alfa-2a) | Roche Pharmaceuticals | Phase IB/II |
| HE2000 | Hollis Eden | Phase II |
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Therapeutic Vaccines |
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|
Product |
Manufacturer |
Status |
| ALVAC (vCP1452) | Aventis Pasteur | Phase II |
| Lipopeptides | Aventis Pasteur/ANRS | Phase II |
| Dermavir | Research Institute for Genetic & Human Therapy (RIGHT) | Pre-clinical |
| VRC-HIVDNA009-00-VP Gag/Pol/Nef/multiclade Envs (A, B, C) | VRC/NIAID | Phase I |
| MVA-BN-Nef | Bavarian Nordic | Phase I |
| MVA-mBN32 | Bavarian Nordic/Epimmune | Phase I |
| MRKAd5 | Merck | Phase I/II |
| MRKDNA | Merck | Phase I |
| VEE replicon | AlphaVax | Phase I in HIV seronegative volunteers |
| Autologous dendritic cells pulsed w/ALVAC | ACTG/Aventis | Phase I |
| Autologous dendritic cell HIV vaccination w/conserved HIV-derived peptides | University of Pittsburgh | Phase I |
| Multi-epitope DNA | Epimmune | Phase I |
| DNA + IL-12 or IL-15 | Wyeth-Ayerst | Pre-clinical |
| Whole-killed (pseudovirions) | Kathy Grovit-Ferbas/UCLA | Pre-clinical |
| HIVAX | Globeimmune | Pre-clinical |
| Tat/Nef/gp120 in ASO2A adjuvant | GlaxoSmithKline | Pre-clinical |
| DNA/MVA | Cobra Pharmaceuticals, Impfstoffwerk Dessau-Tornau GmbH (IDT), Oxford University/MRC | Phase I/II |
| Remune | Immune Response Corporation | Failed phase III, remains under investigation in context of STIs |
| Tat vaccine | Aventis Pasteur | Phase I |
| DNA/fowlpox prime-boost | Virax | Phase I |
| Synthetic peptide immunogens | United Biomedical | Pre-clinical |
| HIV L.E.A.P.S. HIV-1 p17 constructs (L.E.A.P.S. 101B, 101C, 102B and 102C) | Cel-Sci | Pre-clinical |
| GTU-Nef DNA vaccine | FIT-BIOTECH | Phase I |
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Gene Therapies |
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|
Product |
Manufacturer |
Status |
| VRX496 lentiviral vector | VIRxSYS | Phase I |
| Ribozymes (RRz2) | Johnson & Johnson | Phase II |
| HGTV43 | Enzo Biochem | Phase I |
| CD4 T cells transduced with M87o viral entry inhibitor | EUFETS AG | Phase I |
| CD4zeta modified CD4 and CD8 T cells | Cell Genesys | Phase II |
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Cellular Therapies |
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|
Product |
Manufacturer |
Status |
| Activated Cellular Therapy (ACT) | Neoprobe | On hold pending identification of a development partner |
The Also Rans: Hollis-Eden’s Wonder Drug and Good ‘Ole Alpha Interferon
Straddling the boundary between antiretrovirals and IBTs is the approved hepatitis C treatment, pegylated alpha interferon. Alpha interferon appears to have direct antiviral effects and also enhances cell-mediated immune responses in humans. The unpegylated form of alpha interferon was studied for many years as a potential HIV therapy, but eventually abandoned due to underwhelming results. However, the newer pegylated form is now once again being studied as an adjunct to HAART and in the context of treatment interruptions. Another proposed enhancer of cell-mediated immune responses is the DHEA derivative HE2000, but no data has been published on this IBT and many distrust the drug’s developer, Hollis-Eden, who have hyped the results from a small South African study without ever managing to get them into the scientific literature.
Immunosuppressive Agents Gone but Not Forgotten
The association between heightened levels of immune activation and HIV disease progression has led some researchers to pursue studies of several drugs that are typically referred to as “immune suppressants.” These drugs include cyclosporine, prednisone, hydroxyurea and mycophenylate mofetil. All are approved for other indications, and none of the manufacturers is specifically developing these compounds as IBTs. However, academic researchers continue to evaluate their potential, typically as an adjunct to HAART or in the context of treatment interruptions.
CD4 Re-Infusion
Finally, there is a grab bag of approaches involving infusing CD4 T cells that are isolated from HIV-infected individuals, expanded and in some cases genetically modified in the laboratory and then reinfused as a potential IBT. NeoProbe’s Activated Cellular Therapy (ACT) does not involve genetic modification but expands CD4 T cells isolated from the lymph nodes using a technique designed to select the cells secreting HIV-suppressing factors such as beta-chemokines. Despite the publication of intriguing data from a pilot study of the approach, the development of ACT is currently on hold pending identification of commercial partners that might support further research. At least three different biotech companies are attempting to genetically modify CD4 T cells in the lab in order to enhance their resistance to HIV infection, subsequently reinfusing them into the matched HIV-infected donor. A similar approach modifies both CD4 and CD8 T cells in an attempt to improve their ability to restrict HIV replication. Preliminary results from trials of these approaches have shown some limited promise, but it remains uncertain as to whether any of these gene therapy/IBT combinations will eventually enter efficacy trials.
Richard’s IBT pipeline report complete with detailed references will be available shortly at the TAG Web site. A more subjective, big-picture evaluation of the IBT pipeline is to appear in the March issue.